This Application claims the benefit of European Patent Application No. 00 111 377.8 filed May 26, 2000.
The invention relates to an antibacterial aqueous ophthalmic formulation containing ofloxacin as an active ingredient and to the use of chitosan for solubilizing ofloxacin suspended in an aqueous media.
Ofloxacin [i.e. racemic (xc2x1)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid], first disclosed by Daiichi Seiaku CO., LTD in EP-A-0,047,005, is known to be an excellent antibacterial agent which is active against a broad spectrum of gram positive and gram negative organisms.
The high antibacterial action of ofloxacin has been explained by its potent inhibitory activities against DNA gyrase in bacterial cells (Sato K, Inoue Y, Fujii T, Aoyama H, Mitsuhashi S, Infection 1986, 14 Suppl 4:S226-30).
Ofloxacin has been disclosed to be useful for treating a wide variety of bacterial ocular infections by topical administration.
However, due to the poor solubility of ofloxacin which is as low as 3.23 mg/ml at pH of 7.0 [Ross et al, Int. J. Pharm, 63:237-250 (1990)], the use of ofloxacin in ophthalmic formulations meets some problems.
In ophthalmic formulations, solubility of ofloxacin is known to be increased by including additives, in particular surfactants.
However, surfactants are known to cause corneal damage when used for prolonged period.
The solubility of ofloxacin has been disclosed by Ross et al, Int. J. Pharm, 63:237-250 (1990) as being 95,4 mg/ml at pH of 5.0, and the solubility of ofloxacin is further known to be increased by decreasing the pH of the aqueous formulation at a pH close to 5.0, in particular with hydrochloric acid.
EP-A-0,275,515 discloses an aqueous pharmaceutical composition for the treatment of infections in the form of eye-drops comprising an effective amount of S-ofloxacin (levofloxacin) said to be the active and more soluble form of ofloxacin, and an aqueous vehicle such as water in which may be incorporated additives such as surfactants, stabilizers, solubilizers, pH adjusting agents, and so on. The preparation example of eye-drops mentions in particular the use of benzalkonium chloride as a stabilizer and sodium chloride, sodium hydroxide and hydrochloric acid as additives.
An existing collyrium marketed for example in Switzerland under the name Floxal(copyright) and provided from Chauvin, Montpellier, France is presented in the form of a solution containing 0.3% ofloxacin, benzalkonium chloride, and unspecified collyrium additives.
EP-A-0,274,714 discloses an eye ointment for the treatment of infectious eye diseases in the form of a hydrogel containing ofloxacin as active ingredient and carboxymethylcellulose as gelifying agent. Preparation of the ointment requires a step of adjusting the pH of a solution containing ofloxacin at a value of 5.0 to 5.5 with aqueous hydrochloric acid solution and aqueous sodium hydroxide solution.
An object of the present invention is to provide an aqueous ophthalmic formulation containing ofloxacin for curing infections, without problems of tolerance even for prolonged use, which does not contain surfactants and which avoids the steps of adjusting and verifying pH during preparation of the formulation.
Another object of the present invention is to provide the use of a chitosan having a deacetylation degree of 30-90% for solubilizing ofloxacin suspended in an aqueous media having a substantially neutral pH.
According to the present invention, these object have been achieved as a result of the surprising finding that the addition of a chitosan in an aqueous solution containing ofloxacin solubilizes ofloxacin in an optimal way.
Chitosan is known as a chitin derivative obtained by partial to substantial deacetylation of chitin also named poly(N-acetyl-D-glucosamine), which is a naturally occurring biopolymer found in shellfish.
Chitosan contains free amine (xe2x80x94NH2) groups and may be characterised as to the proportion of N-acetyl-D-glucosamine units and D-glucosamine units, and such is expressed as the degree of deacetylation of the fully acetylated polymer chitin.
U.S. Pat. No. 5,422,116 discloses that chitosan having a deacetylation degree of 60 to 99% is useful for preparing a liquid ophthalmic aqueous sustained release delivery system which provides a slow and sustained release of the treating agents incorporated therein to the eye.
In the present invention, an aqueous ophthalmic formulation for the treatment and prevention of infections contains ofloxacin as active ingredient and a chitosan having a deacetylation degree of 30-90% and a molecular weight of 500,000-5,000,000 Da as solubilizing agent of ofloxacin.
The present invention provides an aqueous ophthalmic formulation containing ofloxacin and chitosan without further addition of surfactants or other solubilizing agents or other additives such as pH adjusting agents, which can cure ocular infections, which can be used without problems of tolerance even for a prolonged treatment, and which simultaneously presents increased lachrymal availability and increased time of efficacy with respect to a commercial solution containing ofloxacin.